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Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

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Author: Mooij, M.G. · Duijn, E. van · Knibbe, C.A.J. · Windhorst, A.D. · Hendrikse, N.H. · Vaes, W.H.J. · Spaans, E. · Fabriek, B.O. · Sandman, H. · Grossouw, D. · Hanff, L.M. · Janssen, P.J.J.M. · Koch, B.C.P. · Tibboel, D. · Wildt, S.N. de
Source:Clinical Pharmacokinetics, 11, 53, 1045-1051
Identifier: 522542
doi: doi:10.1007/s40262-014-0176-8
Keywords: Nutrition · Carbon 14 · Drug metabolite · Paracetamol · Accelerator mass spectrometry · Blood sampling · Child · Clinical article · Drug blood level · Drug metabolism · Female · Human · Indwelling catheter · Infant · Limit of quantitation · Liquid chromatography · Male · Mass spectrometry · Maximum plasma concentration · Newborn · Open study · Pharmacokinetics · Pilot study · Preschool child · Priority journal · Single drug dose · Time to maximum plasma concentration · Food and Nutrition · Healthy Living · Life · RAPID - Risk Analysis for Products in Development · ELSS - Earth, Life and Social Sciences


Results: Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C]AAP-4Sul 0.81 (0.29–2.10) ng/L. Dose-normalized oral [14C]AAP Cmax approached median intravenous average concentrations (Cav): 8.41 mg/L (3.75–23.78 mg/L) and 8.87 mg/L (3.45–12.9 mg/L), respectively. Conclusions: We demonstrate the feasibility of using a [14C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children. Background: Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons. Methods: In an open-label microdose pharmacokinetic pilot study, infants (0–6 years of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry. Objective: The objective of this study was to present pilot data of an oral [14C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children.